2-{8 2-(substituted aminomethyl)-4h-1,2,4-triazol-4-yl{9 benzophenones

ABSTRACT

2-(2-(Substitutedaminomethyl)-4H-1,2,4-triazol-4yl)benzophenones of the formula II: ARE DEFINED AS ABOVE. The products of formula II and the pharmacologically acceptable acid addition salts thereof are useful as sedatives and tranquilizers for mammals and birds.   WHEREIN R6 and R7 or together   wherein R1, R2, R3, R4, and R5 are defined as above, and X is chlorine, bromine, or iodine, with an amine of the formula:   IS A HETEROCYCLIC AMINE, E.G. PYRROLIDINO, PIPERIDINO, MORPHOLINO, OR HEXAMETHYLENEIMINO WHICH CAN BE FURTHER SUBSTITUTED WITH ALKYL GROUPS, ARE PREPARED BY CONDENSING A COMPOUND OF FORMULA I:   wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, and cyclopropyl; wherein R2, R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl defined as above, fluorine, chlorine, bromine, nitro, trifluoromethyl, and alkylthio in which alkyl is defined as above; and wherein R6 and R7 are selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms, inclusive, with the proviso that only one of the parameters R6 or R7 can be hydrogen, or together

l mited States Patent Hester, Jr.

[ Dec. 24, 1974 Z-[Z-(SUBSTITUTED AMlNOMETHYL)-4H-l,2,4-TRlAZOL-4- YL]BENZOPHENONES [75] Inventor: Jackson B. Hester, Jr., Galesburg,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

221 Filedz June21, 1973 211 Appl. No.: 372,313

Related US. Application Data [63] Continuation-impart of Ser. No. 240,756, April 3, 1972, abandoned, which is a continuation-in-part of Ser. No. 114,049, Feb. 9, 1971, Pat. No. 3,709,898.

[52] US. Cl... 260/2475 R,,260/2 47.1, 260/293.69,

260/308 R, 424/248, 424/267,'424/269 [51] int. CL. C07d 55/06, C07d 57/00, C07d 99/02 [58] Field of Search..... 260/293.69, 247.1, 247.5 E,

[56] References Cited UNITED STATES PATENTS OTHER PUBLICATIONS Derieg et al., Chem. Abstracts, Vol. 74, Abstract No. l25579e (1971),QD1A51. Gall, Chem. Abstracts, Vol. 78, Abstract No. l36302t (1973),QD1A51. Hester et a1., Chem. Abstracts, Vol. 78, Abstract No. l36354m (1973), QDlASl.

Primary ExaminerAlton D. Rollins 57] ABSTRACT 2-[2-(Substitutedaminomethyl )-4H l ,2,4-triazol-4- yl]benzophenones of the formula II:

is a heterocyclic amine, e.g. pyrrolidino, piperidino, morpholino, or hexamethyleneimino which can be further substituted with alkyl groups, are prepared by condensing a compound of formula I:

wherein R R R R and R are defined as above, and X is chlorine, bromine, or iodine, with an amine of the formula:

e HN wherein R and R or together are defined as above.

The products of formula 11 and the pharmacologically acceptable acid addition salts thereof are useful as sedatives and tranquilizers for mammals and birds.

13 Claims, No Drawings 1 2-[2-(SUBSTITUTED-AMINOMETHYL)-4H-l ,2,4 TRIAZOL-4-YL BENZOPHENONES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of application Ser. No. 240,756 filed Apr. 3, 1972, and now abandoned, which is a continuation-in-part of application Ser. No. 114,049, filed Feb. 9, 1971, now U.S. Pat. No. 3,709,898, granted Jan. 9, 1973.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention is directed to new organic compounds and is particularly concerned with novel 2-[3- (substituted-aminomethyl)r4l-l-1 ,2,4-triazol-4- yllbenzophenones and a process for the production thereof.

The novel compounds of formula 11 and the process of production therefor can be illustratively represented as follows:

wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, and cyclopropyl; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, fluorine, chlorine, bromine, nitro, trifluoromethyl, and alkylthio, in which alkyl is defined as above; and wherein R and R are selected from the group consisting of hydrogen and alkyl of l to 5 carbon atoms, inclusive, with the proviso that only one of the parameters R or R, is hydrogen, or together the group is a heterocyclic amino groupselected from pyrrolidino, piperidino, morpholino, and hexame- -thyleneimino.

The more preferred compounds of this invention are of the formula 11A:

wherein R, is hydrogen or alkyl of 1 to 3 carbon atoms,

inclusive, wherein R R R and R are hydrogen or halogen wherein R and R are selected from the group consisting of hydrogen and alkyl as defined above, with the proviso that only one of the parameters R or R, can be hydrogen or together is selected from the group consisting of pyrrolidino, pi-

peridino, and morpholino, and the pharmacologically acceptable acid salts thereof.

The compounds most preferred have the formula [18:

CH -"N wherein R is hydrogen or methyl; wherein R and R are hydrogen or chlorine, and wherein R is hydrogen, methyl, or ethyl, R is methyl or ethyl to gether piperidino, and morpholino, and the pharmacologically acceptable acid addition salts thereof.

The invention, moreover, encompasses also the pharmacologically acceptable acid salts of the compounds of formula 11 above.

The process of this invention comprises: treating a compound I at a temperature between 0 and 100 C with an amine of the formula are selected from thegroup consisting of pyrrolidino,

herein R and R1 or are defined as above, in an inert organic solvent to give the compound of formula II above.

DESCRIPTION OF THE PREFERRED EMBODIMENT Alkyl groups of l to 3 carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.

Alkylthio can be methylthio, ethylthio, propylthio, and isopropylthio. 1

The compounds of the formulae ll including acid adcontemplated in this invention, are the hydrochlorides,

hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, and the like, prepared by reacting a compound of formula II with an excess of the selected pharmacologically acceptable acid.

Sedative effects of 5-chloro-2-[3- (diethylaminoethyl )-5-methyl-4H-l ,2,4-triazol-4- yllbenzophenone are shown by the following tests in mice:

Chimney test [Med. Exp. 4, 145 (l96l)]: The effective intraperitoneal dosage for 50% of the mice (ED,,,) is 0.6 mgjkg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test Mice in Petri dishes (10 cm. diameter, 5 cm. high,

4 very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicate tranquilization. ED equals the dose of the test compound at which 50% of the mice remain in the dish. The ED (intraperitoneal administration) in this test is 1.0 mgJkg.

Pedestal test The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute. The ED (intraperitoneal administration) for 5-chloro-2-[3-(diethylaminomethyl)- 5-methyl-4H-l,2,4-triazol 4-yl]benzophenone in this test is 1.5 mg./kg.

Nicotine antagonism test Mice in a group of 6 are injected with the test compound, 5-chl0ro-2-[3-(diethylaminomethyl)-5-methyl- 4H-l,2,4-triazol-4-yl]benzophenone. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation, i.e., (1) running con-' vulsions followed by (2)'tonic extensor fits followed by (3) death. An intraperitoneal dosage of 0.2 mg./kg. of the test tgrnpound protected.50% of the mice against and 50- Antagonism to strychnine (as sulfate) The effective dosage (ED50) of 5-chloro-2-[3- (diethylaminomethyl)-5-methyl-4l-ll ,2,4-triazol-4- yllbenz'ophenone is mg./kg. orally in mice. The test consists in orally administering into groups of 6 mice the test compound, and 30 minutes later 3 mg./kg. strychnine sulfate intraperitoneally. The survivors after 4 hours reflect the activity of the compounds as a muscle relaxant and antispasmodic. A dosage of 3 mg./kg. of strychnine sulfate is routinely fatal to all the control mice. The following compounds have an ED (by inpartially embedded in wood shavings), climb out in'a 40 traperitoneal injection) as shown in Table 1 below:

TABLE I COMPOUND Ch D P Ni 5-chloro-2-[ 3-( dimethylaminomethyl )-5-methyl-4H- l ,2,4-triazol-4-yl lbenzophenone; L8 2.2 3.1

2'.5-dichloro-2-[ S-(dimethylaminomethyl)-5-methyl-4H- l .2,4-

triazol-4-yllbenzophenone l l methyl )-5-methyl-4H-l ,2,4-triazol-4-yl1benzophenone I8 22 I00 5.0 S-chloro-Z-l 3-( monomcthylaminomethyl)-5-methyl-4H- l .2,4-triuzol-4-yllbenzophenone 0.3 0.8 0.8

Ch chimney lest D dish test P pedestal test Ni nicotine antagonism (3) test The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral, andrectal use, e.g., tablets, powder packets, cachets, dragees,,capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Water or oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added. 1

For mammals and birds, food premixes, with starch,

oatmeal, dried fishmeat, fishmeal, flour and the like can be prepared. 1

As tranquilizers, the compounds of formula 11 can be used in dosages of 0.1-5.0 mg./kg. in oral or injectable preparations as described above, to alleviate tension and anxiety in mammals, or birds, such as e.g., occurs when animals are in travel.

The starting materials useful for preparing compounds of formula 1 of this application are known in the art, e.g. J. Org. Chem. 26, 4491 (1961), ibid. 27, 3781 (1962); ibid. 30, 521 (1965); ibid. 32, 3798 (1967); J. Pharmaceutical Sciences 61, 2508 (1972) Helv. Chim. Acta 45, 2226 (1962) and US. Pat. No.- 3,121,075. Starting compounds of formula 1 can be prepared from these starting materials as shown in the Preparations.

ln carrying out the process of the present invention, a selected 2-[3-(halomethyl)4H- l,2,4-triazol-4- yl]benzophenone l is reacted with an amine of the formula R6 HV R defined as above Tlie reaction is carried out'in an;inert organic solvent, such as N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide', tetrahydrofuran, dioxane, methylene chloride or the like. Thev starting material and reagents can be in suspension or in solution during the reaction. The amine is used in equivalent amounts or in excess. 1n the preferred em bodiment of this reaction, the reaction-temperature is to 100 C., alkali metal iodide e.g. lithium, sodium- PREPARATlON 1 2'-Benzoyl-4'-chloroacetanilide Acetyl chloride (81.3 g., 1.037 mole) was added to a stirred solution of 2 -amino--chlorobenzophenone (200.0 g., 0.864 mole.) and pyridine (68.4 g., 0.864

mole) in dry ether (4 1.); the mixturewas kept at ambient temperature for 2 hours and treated with 500 ml.

of water. The layers were separated and the ether layer was dried over anhydrous sodium sulfate and concentrated. Crystallization of the residue from ethyl acetate- Skellysolve B hexanes gave:

124.0 gQof 2-benzoyl-4'-chloroacetanilide of melting point 114-1 15 C. Two more crops of 2-benzoyl-4- chloroacetanilide also were obtained: 67.8 g. ofmelting point 113.5114.5 C. and 330g. of melting point 1 13-1 14 C.

PREPARATlON 2 6-Chloro-4-phenyl-2( 1H )-quinoline The procedure (reaction of 2-benzoyl-4- chloroacetanilide with sodium hydroxide) of A. E. Drukker and C. I. Judd, J., Heterocyclic Chem. 3, 359 (1966) was used for this preparation. The yield was 77%. Two other preparations have been described: S.

C. Bell, T. S. Sulkowski, C. Gochman and S. J. Childress, J. Org. Chem. 27,562 (1962): G. A. Reynolds and C. R. Hauser, J. Amer. Chem. Soc. 72, 1842 (1950).

PREPARATION 3 2,6-Dichloro-4-phenylquinoline The procedure of A. E. Drukker andC. l. Judd, J.

Heterocyclic Chem. 3, 359 (1966) was used for this preparation. The yield was 62%.

PREPARATION 4 6-Chloro-2-hydrazino-4-phenylquinoline Anal. calcd. for C H ClN C. 66.79; H, 4.49; Cl. 13.15; N, 15.58. Found: C. 67.15; H, 4.65; C1. 1319; N. 15.32. Preparation 5 7-Chloro-l-methyl-5-phenyl-s-triazolo- [4.3-alquin0line PREPARATION 5 7-Ch1oro-1-methyl-5-pheny1-s-triazo1o-[4,3- a]quino1ine A stirred mixture of 6-chloro-2-hydrazino-4- phenylquinoline (1.4 g., 0.0052 mole), triethyl orthoacetate (0.925 g., 0.0057 mole) and xylene ml.) was refluxed, under nitrogen, for 2 hours and 40 minutes. During this period the ethanol formed in the reac- Anal. calcd. for C H ClN z C, 69.50; H, 4.12; Cl. 12.07; N, 14.31. Found: C, 69.38; H, 4.02; Cl. 12.10. N. 14.49.

7 PREPARATION .6

-Chloro-2-(3-methyl-4H- l ,2,4-triazol-4-yl)- benzophenone (Oxidation of 7-chloro-1-methyl-5-phenyl-s-triazolo[4,3-

a]quinoline) A stirred suspension of 7-ch1oro-1-methyl-5-phenyls-triazolo[4,3-a]quinoline (2.94 g., 0.01 mole) in acetone (110 ml.) was cooled in an ice-bath and treated slowly with a solution prepared by adding sodium periodate (2 g.) to a stirred suspension of ruthenium dioxide (200 mg.) in water (35 ml.). The mixture became dark. Additional sodium periodate (8 g.) was added during the next minutes. The ice bath was removed and the mixture was stirred for 45 minutes. Additional sodium periodate (4 g.) was added and the mixture was stirred at ambient temperature for 18 hours and filtered. The solid was washed with acetone and the combined filtrate was concentrated in vacuo. The residue was suspended in water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. The residue was chromatographed on silica gel (100 g.) with 10% of methanol-90% ethyl acetate; 50 ml. fractions were collected. The product was eluted in fractions 10-20 and was crystallized from ethyl acetate to give: 0.405 g. of 5-chloro-2-( 3-methyl-4l-ll ,2,4-triazol-4- yl)benzophenone .of melting point 168-l69.5 C. and 0.291 g. of melting point 167.59-169. (23.4% yield). The analytical sample had a melting point of 168 C.

Anal. calcd. for C H CIN O:

. 6;Cl,ll.9l;N.l Found: C. 64.56; H. 4.35; CI. 11.97; 11.9

PREPARATION 7 A stirred suspension of 7-chloro-l-methyl-5-phenyls-triazo'lo[4,3-alquinoline (2.94 g., 0.01 mole) and acetone (200-ml.) was cooled in an ice bath and treated, dropwise, during 16 minutes with a solution prepared from ruthenium dioxide (200 mg.), sodium periodate (4g.) and water (35 ml.). A slight exothermic reaction was noted and the mixture became dark. After 10 minutes 29 ml. of a solution of sodium periodate (12 g.) in water (70 ml.) was added during 10 minutes. This mixture was stirred for 2 hours and then the remaining sodium periodate solution (41 ml.) was added during the next 3 hours. The mixture was concentrated in vacuo to remove acetone. The resulting aqueous'mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residuewas chromatographed on silica gel (150 g.) with 2%.methanol 98% chloroform; 60 ml. fractions were collectedJRecovered starting material was eluted in fractions .1 1-14 and crystallized from methanol-methylene chloride to give 0.069 g. of melting point 251.5-:253.5 C. A mixture of thetwo products was eluted in fractions 15-39,

Crystallization of this mixture from ethyl acetate gave 618 mg. (20.8%) of 5-chloro-2-(3-methyl-41-l-1,2,4- triazol-4-yl)benzophenone of melting point l65.5-168.

3 PREPARATION s Oxidation of 7-jchlorol -methyl-5-phenyl-s-triazolo[4,3-a]quinoline A vigorous stream of ozone in oxygen was bubbled for 12 hours, into a stirred, ice-cold solution of 7- chloro-l-methyl-5-phenyl-s-triazolo[4,3-alquinoline (31.1 g., 0.106 mole) in'methanol (750ml.) and methylene chloride (500 ml.). The resulting mixture was filtered and the filtrate was added to an ice cold solution of sodium iodide (47.5 g.) and acetic acid (63 ml) in water (200 ml.). The solution was decolorized by the addition of sodium thiosulfate and concentrated in vacuo. The residue was mixed with water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1.5- kg); 175 ml. fractions were collected. Fractions 1 to 128 were eluted with 1% methanol-99% chloroform and fractions 129-168 with 5% methanol-% chloroform. The first compound was eluted in fractions 49-60 and crystallized from methanol-ethyl acetate to give: 0.769 g. of melting point 229.523l (decomposition) of 7-chl0ro-l-methyl-5- phenyl-s-triazolo[4,3-a]quinolin-4(5H)-one. The analytical sample had a melting point 232-233 C.

Anal. calcd. for C, ,H ClN,O:

C, 65.92; Hv 3.

91 Found: C, 65.46; H. 3.72; Cl

;Cl. 11.44;N, 13.57.

Recovered starting material was eluted in fractions 66-78 and crystallized from methylene chloridemethanol to give 0.737 g. of melting point 251-2535 C. A mixture of two remaining products was eluted in fractions 73-168. Crystallization of this mixture from ethyl acetate gave: 10.8 g. of melting point 166.5 -l67.5 C., 0.987 g.,of melting point 166-167' C. and 2.52 g. of melting point 164-165.5 C. (45.3% yield) of 5-chloro-2-(3-methyl-4H-l,2,4-triazol 4- yl)benzophenone.

formaldehyde (3g.-) and xylene ml.) was warmed under nitrogen, in a bath maintained at C. for 7 hours. The mixture was then concentrated in vacuo. The residue'was chromatographed on silica gel g.) with 3% methanol 97% chloroform. Fifty milliliter fractions were collected. The product was eluted in fractions 20 to 44. The fractions were concentrated and the residue was crystallized from ethanol-ethyl acetate to give:'l.64 g. of melting point 138-142 C.; 0.316 g. of melting point 138.5-141 C.; 0.431 g. of melting point 139-14l C. (72.8% yield) of 5-chloro-2-[3- (hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4- yllbenzophenoneThe analytical sample'had a melting point of 138-l39 C. f

PREPARATlON 5-Chloro-2-[ 3-( bromomethyl )-5-methyl-4H- 1 .2.4- triazol-4-yllbenzophenone A solution of 5-chloro-2-[3-(hydroxymethyl)-5- methyl-4H-l,2,4-triazol4-yl]benzophenone (328 mg., 0.00] mole) in dry. hydrocarbon-stabilized chloroform (5ml.) was cooled in an ice bath and treated with phosphorus tribromide (0.1 mol.). The colorless solution vwas kept in the ice bath for 55 minutes and at ambient temperature (22-24". C.) for 5 hours. The resulting yellow solution was poured into a mixture of ice and dilute sodium bicarbonate. This mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give: 0.285 g. of melting point 200-240 (decomposition) and 0.0030 g. melting point 200-220 C. (decomposition) of 5-chloro-2-[3- (bromomethyl)-5-methyl-4l-1-l,2,4-triazol-4- yl]benzophenone. The analytical sample hald a melting point of 200-240 C. (decomposition).

Anal. calcd. for C H BrClN O:

C. 52.26; H. 3.35; Br. 20.46; Cl. 9.08; N. 10.76. Found: C. 52.13; 52.45; H. 3.77; 3.66; Br. 20.44; Cl.

PREPARATION ll 5-Chloro-2-[ 3-(chloromethyl)-5-methyl-4H-l ,2,4-- triazol-4-yl]benzophenone A solution of 5-chloro-2-[3-(hydroxymethyl)-5- methyl-4H-l.2,4-triazol-4-yl]benzophenone (328 mg. 0.001 mole) in thionyl chloride (2ml.') was warmed during 40 min. to a bath temperature of /8 C. and kept at 78-83 C. for 1 hour minutes. It was then cooled and poured into ice water. This mixture was neutralized with sodium bicarbonate and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate Skellysolve B hexanes to give: 0.240 g. of 5-chloro-2- [3-(chloromethyl )-5-r nethyl-4H-l ,2,4-triazol-4- yl]benzophenone of melting point 144.5' l47 C. and 0.045 g. of melting point l44.5l,46 .5 C. The analytical sample had a melting point of l39-l40 C.

Anal. calcd. for c H- cl N o;

. c. 58.76; H. 3.72. c1. 20.48; N. 12.14. Found: c. 59.22; H. 3.80; ct. 20.66; N. 11.91.

PREPARATION 12 5 -Chloro-2-[3-iodomethyl)-5-methyl-41 l-1.2,4-triazol- 4-yl]benzophenone with chloroform. The extract was washed with brine. dried and concentrated. The residue was crystallized from methylene chloride-ethyl acetate to give: 0.227 g. of 5-chlor0-2-[ 3-( iodomethyl)-5-methyl-4H- l .2.4- triazol-4-yllbenzophenone of melting point l85.5-l 885 (decomposition). The analytical sample had a melting point of 185-200 C. (decomposition).

Anal. calcd. for c,,H..ci1N.o;

c. 46.65; H. 2.99; 01, 8.10; 1. 29.00; N. 9.60. Found: c, 46.78; H. 2.88; CI. 8.59; 1. 26.98; N. 9.23.

In the manner given in the prior preparations other 2-[3-(halomethyl)-4H-l,2,4-triazol-4- yl]benzophenones can be synthetized, such as:

2, 5-dichloro-2-l3-(chloromethyl)-5-m'ethyl-4H- l,2,4-triazol-4-yl]benzophenone; 2'-chloro-2-[3-(bromomethyl)-5-methyl-4H-l,2,4-

triazol-4-yl]benzophenone; 2,6'-difluoro-5-chloro-2-l3 -(iodomethyl)-5-methyl- 4H-l,2,4-triazol-4-yllbenzophenone;

5-nitro-4-trifluoromethyl-2-[3-(chloromethyl)-4H- 1,2,4-triazol-4-yllbenzophenone; 2,5-dichloro-2-[3-(chloromethyl)-5-methyl-4H- 1,2,4-triazol-4-yl]benzophen'one; 6-ethylthio-2',4'-dimethyl-2-[3-(iodomethyl)5-ethyl- 4H-l ,2,4-triazol-4-yl]benzophenone; 5,6-dibromo-3'-amino-2-[3-(chloromethyl)-5-ethyl- 4H-l ,2,4-triazol-4-ylIbenzophenone; 5-ethyl-2,4-dipropyl-2-[3-(chloromethyl)-5- methyl- 1 ,2.4-triazol-4-yllbenzophenone;

2',5-dibromo-2-[ 3-(chloromethyl)-5-ethyl-4H-l .2.4-

triazol-4 yllbenzophenone; 3-propylthio-4'-propyl-2-[3-(bromomethyl)-5- methyl-4H-1,2,4-triazol-4-yl]benzophenone; 4-isopr0pyl-5-bromo-3-ethyl-2-[3-(bromomethyl)-5- propyl-4H-1,2.4-triazol-4-yl]benzophenone; and the like.

EXAMPLE 1 5-Chloro-2-[3-(diethylaminoethyl)-5-methy1-4H- l,2,4-triazol-4-yl]benzophenone A stirred suspension 2 of 5-chloro-2-[3- (bromomethyl)-5-methyl-4H-1,2,4-triazol-4- yl]benzophenone (1.16 g. 0.00297 mole) in tetrahydrofuran (45 ml.) was cooled in an ice bath, under nitrogen, and treated with a solution of diethylamine (6 ml.) in methanol (15 ml.). The mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was mixed with water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated.

Crystallization of the residue from ethyl acetate Skelly- A solve B hexanes gave 0.97 g. of 5-chloro-2-[3- (diethylaminomethyl)-5-methyl-4l-l-l .2,4-triazol-4- yl]benzophenone of melting point 'l10 .5ll1.5 C.

0 The analytical sample had a melting point of 1 12-l 13 EXAMPLE 2 S-Chloro-Z-l 3-(dimethylaminomethyl )--methyl-4H- 1,2,4-triazo1-4-yl]benzophenone A stirred suspension of 5-chloro-2-[ 3- (bromomethyl )-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone (1.0 g., 0.00256 mole) in tetrahydro furan (40 ml.) was cooled in an ice bath and treated with 32 ml. of a saturated solution of dimethylamine in methanol. The mixture was removed from the ice bath, stirred at ambient temperature for 30 minutes and concentrated in vacuo. The residue was mixed with water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. Crystallization of the residue from ethyl acetate gave 0.52 g. of 5-chlor0-2-[3-(dimethylaminomethyl)- 5-methyl-4H- l ,2,4-triazol-4-yl]benzophenone of melting point 171172 C. and 0.14 g. of melting point l68-170 C.

Anal. calcd. for C H CINQ:

C. 64.31; H. 5.50; Cl. 9.99; N. 15.79. Found: C. 63.99: H. 5.49; Cl. 9.96; N. 15.57.

EXAMPLE 3 5-Chloro-2-[3-(methylaminomethyl)-5-methyl-4H- 1,2,4-triazol-4-yl ]benzophenone A stirred suspension of 5-chloro-2-[3- (bromomethyl)-5-methyl-4l-1-1,2,4-triazol-4- yl]benzophenone 1.4 g., 0.00358 mole) in tetrahydrofuran (53 ml.) was cooled in an ice bath and treated with 45 ml. of a saturated solution of methylamine in methanol. The mixture was removed from the ice bath, stirredat ambient temperature for-30 min. and concentrated in vacuo. The residue was mixed with water and extracted with methylene chloride. The extract was dried over anhydrous potassium carbonate and concentrated. Crystallization of the residue from ethyl acetate gave 0.97 g. of 5-chloro-2-[3 (methylaminomethyl)-5- methyl-4H-1,2,4-triazol-4-yl]benzophenone of melting point 174-175 C. The analytical sample had a melting point of l75176 C.

Anal. calcd. for C H CIN O:

C. 63.43; H. 5.03;C1,10.40;N.16.44. Found: C. 63.43; H, 5.14; C1, 10.49; N. 16.52.

EXAMPLE 4 2 ,5-dichloro-2-[ 3-(dimethylaminomethyl )-5-methyl- 4H-l ,2,4-triazol-4-yl]benzophenone Anal. calcd. for C H CI N O: C, 58.62; H,

4.66; N, 14.40; Cl. 18.21. Found: C. 58.50; H, 4.57; Ni

2,5-dichloro-2-[3-(dimethylaminomethyl)-5- 'cyclopropyl-4H-l ,2,4-triazol-4-yl]benzophenone 7 12 EXAMPLE 5 2',5-Dichloro-2-[ 3-( dimcthylaminomethyl )-5- cyclopropyl-4H-1,2,4-triazol-4-y|]benzophenone 1n the manner given in Example 1, 2,5-dichloro-2- [3-(chloromethyl)-5-cyclopropy1-4H-l ,2,4-triazol-4- yll-benzophenone was reacted with dimethylamine to give 2,5-dichloro-2-[3-(dimethylaminomethyl)-5- of melting point l091 15 C.

Anal. calcd. for C H CI MO:

C, 60.73; H, 4.85; N. 13.49; C1; 17.07. Found: C, 60.64; H, 4.86; N, 13.61; C1. 17.17.

EXAMPLE 6 2'-Chloro-2-[S-(dimethylaminomethyl)-5-methyl-4l-1- 1,2,4-triazo1-4-yl]benzophenone 1n the manner given in Example 1, 2-chloro-2-[3- (bromomethyl)-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone was reacted with dimethylamine to give 2-chloro-2-[3-(dimethy1aminomethyl)-5-methyl- 4H-l,2,4-triazo1-4-yl]benzophenone of melting point 147-l 50 C.

Anal. calcd. for C H CIMO:

C, 64.31; H, 5.40; N, 15.79; Cl. 9.99. Found: C, 64.15; H. 5.34; N. 15.75; C1. 10.08.

EXAMPLE 7 5-Chloro-2-[3-(pyrrolidinomethyl)-5-methyl-4H- 1,2,4-triaz0l-4-yl]benzophenone 1n the manner given in Example 1, 5-chloro-2-[3- (iodomethyl)-5-methyl-4H- l ,2,4-triazol-4- yl]benzophenone was reacted with pyrrolidine to give 5-chloro-2-[3-(pyrrolidinomethyl )-5-methyl-4H-l ,2,4-

5-Chloro-2-[3-(morpholinomethyl)-5-methyl 4H- 1,2,4-triazol-4-yl]benzophenone 1n the manner given in Example 1, 5-chloro-2-[3- (bromomethyl)-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone was reacted with morpholine to give 5-chloro-2-[3-(morpholinomethyl)-5-methyl-4H- 1,2,4-triazol-4-yl]benzophenone of melting point 128.5130.5 C.

Anal. calcd. for C, H,,C1N O,:

C. 63.56; H. 5.34; N. 14.

12;Cl. 3. Found: C, 63.41;H,5.37;N, 14.21;C1. 8

EXAMPLE 9 -Chloro'2-[3a(piperidinomethyl)-5-methyl-4H-1,2,4- triazol-4-yl]benzophenone hydrochloride In the manner given in Example 1, 5-chloro-2-[3- (bromomethyl )-5-methyl-4H-1 ,2,4-triazo1-4- yl]benzophenone was reacted with piperidine to give 5-chloro-2-[3-(piperidinomethyl)-5-methyl-4H-l,2,4- triazol-4-yl]benzophenone which was treated with hydrochloric acid in ether tov give the corresponding salt of melting point 228-240 C. (dec.).

EXAMPLE 2',5-Dichloro-2-[ 3-(pyrrolidinomethyl)-5-methyl-4H- 1,2,4-triazol 4-yl]benzophenone In the manner given in Example 1, 2,5-dichloro-2-' [3-(bromomethyl)-5methyl-4H-1,2,4-triazol-4' yl]benzophenone was reacted with pyrrolidine to give 2,5-dichloro-2-[3-(pyrrolidinomethyl)-5-methyl-4H- 1,2,4-triazol-4-yl]benzophenone of melting point 131-132 C. 1

Analv calcd, for C H CI MO:

C, 60,75; H. 4.86; N. Found: C, 6055, H, 4. 4; N.

13.40; Cl, 17.07. 1341; C1, 16.66.

EXAMPLE 1 1 6-ethylthio-2-[3-(hexamethyleneiminomethyl)-5- ethyl-4H- 1 ,2,4-triazol-4-yl]benzophenone In the manner given in Example 1, 6-ethylthio-2-[3- (iodomethyl)-5-ethyl-4l-I-1,2,4-triazol-4- yl]benzophenone was reacted with hexamethyleneimine to give 6-ethylthio-2-l 3- (hexamethyleneiminomethyl)-5-ethyl-4H-1,2,4 triazol-4'yllbenzophenone.

EXAMPLE l2 5-Bromo-3'-ethyl-4-isopropyl-2-[ 3- (ethylaminomethyl)-5-propyl-4l-I-1,2,4-triazol-4 yl lbenzophenone In the manner given in Example 1, 5-bromo-3-ethyl- 4-isopropyl-2-[3-(bromomethyl)-5-propyI-4l-I-l ,2,4- triazol-4-yl]benzophenone was reacted with ethylamine to give 5-bromo-3-ethyl-4-isopropyl-2-[3- (ethylaminomethyl)-5-propyl-4H-1 ,2,4-triazol-4- yllbenzophenone.

EXAMPLE 13 3 -Br0mo-4-propyl-2-[3-(morpholinornethyl -5- isopropyl-4I-l-1,2,4-triazol-4-yllbenzophenone defined as above. Representative compounds, thus obtained, include:

2',6'-difluoro-5-chloro-2-[3-(diethylaminomethyl)- S-methyl-l ,2,4-triazol-4-yl ]benzophenone; 5-nitro-4'-trifluoromethyl-2-[3-(piperidinomethyl)- 1,2,4-triaz0l-4-yl]benzophenone; 5,6-dibromo-3-amino-2-[3-(dimethylaminomethyl)- 5-ethyl-I,2,4-triazol-4-yl]benzophenone; 5-(diethylamino)-2',4-dipropyl-2-[3- (ethylaminomethyl)-5-methyl-1 ,2,4-triazol-4- yl]benzophenone;

(diethylaminomethyl)-5-methyl-1,2,4-triazol-4- yl] benzophenone; 3-propylthio-4'-propyl-2-[3-(morpholinomethyl)-5- methyl-l,2,4-triazol-4-yl]benzophenone; and the like.

Treating the compounds of formula II (including compound HA and 118) with pharmacologically acceptable acid such as hydrochloric, hydrobromic, phos phoric, sulfuric, acetic, propionic, toluenesulfonic, methanesulfonic, tartaric, citric, lactic, malic, maleic, cyclohexanesulfamic acids, produces the pharmacologically acceptable salts of these compounds of formula II which can be used like the free base compounds of formula 11. Salt formation is achieved in conventional manner by reacting the compounds of formula II with excess of a selected acid in a suitable medium e.g. water, a lower alkanol, ether, or acetone and recovering the salt by evaporating the solvent, preferably in vacuo.

I claim:

11. A 2-[3-(substitutedaminornethyllAH-l,2,4- triazol-Z-yllbenzophenone of the formula II:

methyl, and alkylthio in which alkyl is defined as above;

and wherein R and R, are selected from the group consisting of hydrogen and alkyl of l to 5 carbon atoms, inclusive, with the proviso that only one of the parameters R or R, can be hydrogen, or together the group is a heterocyclic amino group selected from pyr rolidino, piperidino, morpholino, and hexame- .thyleneimino, and the pharmacologically acceptable acid addition salts thereof.

2. A compound according to claim I of the formula HA wherein R, is alkyl of l to 3 carbon atoms, inclusive;

' wherein R R,', R,, and R are hydrogen, fluorine,

chlorine or bromine; wherein R and R, are selected from the group consisting of hydrogen and alkyl as defined above, with the proviso that only one of the parameters R or R, can be hydrogen, or together is selected from the group consisting of pyrrolidino, pi-

peridino, and morpholino, and the pharmacologically acceptable acid salts thereof.

3. A compound according to claim 1 of the formula wherein R," is methyl; wherein R and R," are hydrogen or chlorine, and wherein R is hydrogen, methyl, or ethyl, R," is methyl or ethyl or together are selected from the group consisting of pyrrolidino, piperidino, and morpholino, and the pharmacologically acceptable acid addition salts thereof.

4. The compound according to claim 3 wherein R, is methyl, R is hydrogen, R, is chloro, R and R are ethyl, and the compound is therefore -chloro-2- l3-(diethylaminomethyl )-5-methyl-4H- l ,2,4-triazol-4- yl]benzophenone.

5. The compound according to claim 3 wherein R," is methyl, R is hydrogen, R," is chloro, R," and R are methyl and the compound is therefore 5-chloro-2- [3-(dimethylaminomethyl )-5-methyl-4H- l ,2,4-triazo|- 4-yl]benzophenone. I

6. The compound according to claim 3 wherein R," is methyl, R and R are hydrogen, R, is chloro, R," is methyl and the compound is therefore 5-chloro- 2-[3-(methylaminomethyl)-5-methyl-4H-1,2,4-triazol- 4-yllbenzophenone.

7. The compound according to claim 3, wherein R," is methyl, R and R, are chloro, R and R," are methyl and the compound is therefore 2',5-dichloro-2- [3-(dimethylaminomethyl)-5-methyl-4Hl ,2,4-triazol- 4-yllbenzophenone.

8. The compound according to claim 1, wherein R, is cyclopropyl, R and R are hydrogen, R is o-chloro, R, is 5-chloro, R and R are methyl and the compound is therefore 2',5-dichloro-2-[3- (dimethylaminomethyl)-5-cyclopropyl-4H-l ,2,4- triazol-4-yllbenzophenone.

9. The compound according to claim 3 wherein R, is methyl, R, is hydrogen, R is chloro, R and R are methyl and the compound is therefore 2-chloro-2- [3-(dimethylaminomethyl)-5-methyl-4H-l ,2,4-triazol- 4-yl]benzophenone.

10. The compound according to claim 3 wherein R," is methyl, R is hydrogen, R," is chloro, N/Rell \R7Il is pyrrolidino and the compound is therefore 5-chloro- 2-[3-(pyrrolidinomethyl)-5-methyl-4H-l,2,4-triazol-4- yl]benzophenone.

11. The compound according to claim 3 wherein R," is methyl, R is hydrogen, R," is chloro,

/Rell 7n is morpholino and the compound is therefore 5-chloro- 2-[3-(morpholinomethyl)-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone.

12. The compound according to claim 3 as the hydrochloride wherein R," is methyl, R is hydrogen, R, is chloro,

/R6l| -N R7II is piperidino and the compound is therefore 5-chloro- 2-l 3-(piperidinomethyl)-5-methyl-4H-l ,2,4-triazol-4- yl]benzophenone hydrochloride.

13. The compound according to claim 3 wherein R,"

is methyl, R is chloro, R, is chloro,

is pyrrolidino and the compound is therefore 2',5- dichloro-Z-l 3-(pyrrolidinomethyl )-5-methyl-4Hv-l ,2,4-

triazol-4-yl lbenzophenone. 

1. A 2-(3-(SUBSTITUTEDAMINOMETHYL)-4H-1,2,4-TRIAZOL-4YL)BENZOPHENONE OF THE FORMULA II:
 2. A compound according to claim 1 of the formula IIA
 3. A compound according to claim 1 of the formula
 4. The compound according to claim 3 wherein R1'''' is methyl, R2'''' is hydrogen, R4'''' is chloro, R6'''' and R7'''' are ethyl, and the compound is therefore 5-chloro-2-(3-(diethylaminomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 5. The compound according to claim 3 wherein R1'''' is methyl, R2'''' is hydrogen, R4'''' is chloro, R6'''' and R7'''' are methyl and the compound is therefore 5-chloro-2-(3-(dimethylaminomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 6. The compound according to claim 3 wherein R1'''' is methyl, R2'''' and R6'''' are hydrogen, R4'''' is chloro, R7'''' is methyl and the compound is therefore 5-chloro-2-(3-(methylaminomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 7. The compound according to claim 3, wherein R1'''' is methyl, R2'''' and R4'''' are chloro, R6'''' and R7'''' are methyl and the compound is therefore 2'',5-dichloro-2-(3-(dimethylaminomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 8. The compound according to claim 1, wherein R1 is cyclopropyl, R3 and R5 are hydrogen, R2 is o-chloro, R4 is 5-chloro, R6 and R7 are methyl and the compound is therefore 2'',5-dichloro-2-(3-(dimethylaminomethyl)-5-cyclopropyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 9. The compound according to claim 3 wherein R1'''' is methyl, R4'''' is hydrogen, R2'''' is chloro, R6'''' and R7'''' are methyl and the compound is therefore 2''-chloro-2-(3-(dimethylaminomethyl)-5-methyl-4H-1,2,4-triazol-4 -yl)benzophenone.
 10. The compound according to claim 3 wherein R1'''' is methyl, R2'''' is hydrogen, R4'''' is chloro,
 11. The compound according to claim 3 wherein R1'''' is methyl, R2'''' is hydrogen, R4'''' is chloro,
 12. The compound according to claim 3 as the hydrochloride wherein R1'''' is methyl, R2'''' is hydrogen, R4'''' is chloro,
 13. The compound according to claim 3 wherein R1'''' is methyl, R2'''' is chloro, R4'''' is chloro, 